Characteristics of Latent Autoimmune Diabetes in China
Of 287 (5.9%) LADA cases, there was no sex difference (6.1% [178 of 2,906] male vs. 5.5% [109 of 1,974] female, P = 0.302). LADA frequency was not significantly age related when divided into four age subgroups (30–39, 40–49, 50–59, and ≥60 years old), even after adjustment for geography, ethnicity, sex, and BMI (P = 0.19). Among these 4,880 subjects, the different frequency of LADA in Han compared with other ethnic groups (5.9% [284 of 4,786] vs. 3.2% [3 of 94], respectively) was not significant (P = 0.322).
To examine geographic variation in the prevalence of LADA, we divided Mainland China geographically along the Qin Mountain-Huai River into Southern China (with 16 cities, 27 hospitals, and 2,746 patients) and northern China (10 cities, 19 hospitals, and 2,117 patients). After adjustment for ethnicity, age, sex, and BMI, there was a significant difference between northern and southern China for LADA (6.5% [137 of 2,119] vs. 5.4% [150 of 2,761], P = 0.040). Frequency of LADA was highest in northeastern China (7.1% [58 of 815]), which has the highest latitude and coldest climate, and lowest in southwestern China (4.0% [20 of 502], P = 0.019) (Fig. 2).
(Enlarge Image)
Figure 2.
China map for LADA China Study.
, cities from the northeastern part of China;
, cities from the northern part of China;
, cities from northwestern China;
, cities from eastern China;
, cities from central China;
, cities from southern China; and
, cities from southwestern China. LADA frequency was higher in northern than southern China after age, sex, and BMI adjustment ( P < 0.040). (A high-quality color representation of this figure is available in the online issue.)
Compared with type 2 diabetic patients, LADA patients (Table 1) were leaner (BMI 23.9 ± 3.7 vs. 24.8 ± 3.4 kg/m, P < 0.001; waist circumference 85.2 ± 10.6 vs. 88.1 ± 9.9 cm, P < 0.001) with lower β-cell function (FCP 0.45 ng/mL [interquartile range 0.01–3.34] vs. 0.64 ng/mL [0.01–4.96], P < 0.001) and less hypertriglyceridemia (62.4 vs. 69.8%, P = 0.008), hypertension (34.1 vs. 42.4%, P = 0.007), obesity (35.9 vs. 44.6%, P = 0.005), and metabolic syndrome (MetS) (62.0 vs. 75.6%, P < 0.001).
Compared with northern LADA patients, the southern LADA patients were leaner (BMI 23.1 ± 3.5 vs. 24.9 ± 3.8 kg/m, P < 0.001; waist circumference 82.9 ± 10.2 vs. 87.7 ± 10.5 cm, P < 0.001), with less MetS (52.0% [78 of 150] vs. 73.0% [100 of 137], P < 0.001) and, importantly, had a higher GADA titer (0.1195 [0.06–1.50] vs. 0.089 [0.06–1.29], P = 0.037). Of note, β-cell function showed no significant differences between northern and southern subjects for either LADA or type 2 diabetes (data not shown).
To analyze the distribution of GADA titer in LADA, we log transformed the data, which showed a possible bimodal distribution (Fig. 3). GADA positivity above or below 180 units/mL largely captured the two modes, with high GADA titer (≥180 units/mL) in 26.5% of patients (76 of 287) and a low GADA titer (<180 units/mL) in 73.5% (211 of 287). High GADA titer LADA subjects compared with low GADA titer LADA subjects were younger at diagnosis (48.1 ± 12.3 vs. 51.2 ± 11.5 years, P = 0.036) and leaner (BMI 22.3 ± 3.2 vs. 24.5 ± 3.7 kg/m, P < 0.001, and waist circumference 80.1 ± 8.6 vs. 87.0 ± 10.7 cm, P < 0.001), with lower blood pressure (systolic 117.8 ± 15.8 vs. 126.3 ± 17.5 mmHg, P < 0.001; diastolic 75.3 ± 9.2 vs. 80.0 ± 10.0 mmHg, P = 0.001), lower triglyceride levels (1.17 mmol/L [0.06–6.88] vs. 1.61 mmol/L [0.15–14.99], P < 0.001), lower insulin secretion (FCP 0.32 ng/mL [0.01–1.57] vs. 0.51 [0.11–3.34], P < 0.001), and less MetS (39.5 vs. 70.1%, P < 0.001). However, when low GADA titer LADA were compared with type 2 diabetic patients (GADA-negative patients), with the exception of HDL cholesterol (1.26 ± 0.54 vs. 1.34 ± 0.70 mmol/L, P = 0.044), clinical features between them were not significantly different (Table 2).
(Enlarge Image)
Figure 3.
Bimodal GADA titer (log 10 transformed) in LADA patients. GADA positivity above or below 180 units/mL largely captured the two modes, with high GADA titer (≥180 units/mL) in 26.5% of patients (76 of 287) and a low GADA titer (<180 units/mL) in 73.5% (211 of 287).
In these Chinese patients, as for Europeans, the frequency of total diabetes-susceptibility haplotypes (i.e., DQA1*03-DQB1*0302, DQA1*03-DQB1*0303, DQA1*03-DQB1*0401, and DQA1*05-DQB1*0201) was significantly higher in LADA (63.9% [115 of 180]) than in both type 2 diabetic (47.1% [82 of 174]) and control (43.2% [214 of 495]) subjects, while the frequency of diabetes-protective haplotypes (i.e., DQA1*0102-DQB1*0601, DQA1*0102-DQB1*0602, and DQA1*0601-DQB1*0301) in LADA (22.8% [41 of 180]) was significantly lower than in both type 2 diabetic (33.3% [58 of 174]) and control (32.7% [162 of 495]) subjects (Table 3). The frequency of HLA-DQ diabetes-susceptibility DQA1*05-DQB1*0201 was greater in high GADA titer than in low GADA titer patients (38.8% [19 of 49] vs. 13.7% [18 of 131], respectively, P < 0.001]) (Table 3). Comparing subjects from the south and north of China, LADA subjects had a similar frequency of HLA-DQ diabetes-susceptibility (69.3% [70 of 101] vs. 57.0% [45 of 79], respectively) and diabetes-protective (18.8% [19 of 101] vs. 27.8% [22 of 79], respectively) haplotypes (Table 4).
Results
Frequency of GADA Positivity and LADA in China
Of 287 (5.9%) LADA cases, there was no sex difference (6.1% [178 of 2,906] male vs. 5.5% [109 of 1,974] female, P = 0.302). LADA frequency was not significantly age related when divided into four age subgroups (30–39, 40–49, 50–59, and ≥60 years old), even after adjustment for geography, ethnicity, sex, and BMI (P = 0.19). Among these 4,880 subjects, the different frequency of LADA in Han compared with other ethnic groups (5.9% [284 of 4,786] vs. 3.2% [3 of 94], respectively) was not significant (P = 0.322).
Geographic Distribution of LADA
To examine geographic variation in the prevalence of LADA, we divided Mainland China geographically along the Qin Mountain-Huai River into Southern China (with 16 cities, 27 hospitals, and 2,746 patients) and northern China (10 cities, 19 hospitals, and 2,117 patients). After adjustment for ethnicity, age, sex, and BMI, there was a significant difference between northern and southern China for LADA (6.5% [137 of 2,119] vs. 5.4% [150 of 2,761], P = 0.040). Frequency of LADA was highest in northeastern China (7.1% [58 of 815]), which has the highest latitude and coldest climate, and lowest in southwestern China (4.0% [20 of 502], P = 0.019) (Fig. 2).
(Enlarge Image)
Figure 2.
China map for LADA China Study.
, cities from the northeastern part of China;
, cities from the northern part of China;
, cities from northwestern China;
, cities from eastern China;
, cities from central China;
, cities from southern China; and
, cities from southwestern China. LADA frequency was higher in northern than southern China after age, sex, and BMI adjustment ( P < 0.040). (A high-quality color representation of this figure is available in the online issue.)
Clinical characteristics of LADA
Compared with type 2 diabetic patients, LADA patients (Table 1) were leaner (BMI 23.9 ± 3.7 vs. 24.8 ± 3.4 kg/m, P < 0.001; waist circumference 85.2 ± 10.6 vs. 88.1 ± 9.9 cm, P < 0.001) with lower β-cell function (FCP 0.45 ng/mL [interquartile range 0.01–3.34] vs. 0.64 ng/mL [0.01–4.96], P < 0.001) and less hypertriglyceridemia (62.4 vs. 69.8%, P = 0.008), hypertension (34.1 vs. 42.4%, P = 0.007), obesity (35.9 vs. 44.6%, P = 0.005), and metabolic syndrome (MetS) (62.0 vs. 75.6%, P < 0.001).
Compared with northern LADA patients, the southern LADA patients were leaner (BMI 23.1 ± 3.5 vs. 24.9 ± 3.8 kg/m, P < 0.001; waist circumference 82.9 ± 10.2 vs. 87.7 ± 10.5 cm, P < 0.001), with less MetS (52.0% [78 of 150] vs. 73.0% [100 of 137], P < 0.001) and, importantly, had a higher GADA titer (0.1195 [0.06–1.50] vs. 0.089 [0.06–1.29], P = 0.037). Of note, β-cell function showed no significant differences between northern and southern subjects for either LADA or type 2 diabetes (data not shown).
Clinical Characteristics According to GADA Titer
To analyze the distribution of GADA titer in LADA, we log transformed the data, which showed a possible bimodal distribution (Fig. 3). GADA positivity above or below 180 units/mL largely captured the two modes, with high GADA titer (≥180 units/mL) in 26.5% of patients (76 of 287) and a low GADA titer (<180 units/mL) in 73.5% (211 of 287). High GADA titer LADA subjects compared with low GADA titer LADA subjects were younger at diagnosis (48.1 ± 12.3 vs. 51.2 ± 11.5 years, P = 0.036) and leaner (BMI 22.3 ± 3.2 vs. 24.5 ± 3.7 kg/m, P < 0.001, and waist circumference 80.1 ± 8.6 vs. 87.0 ± 10.7 cm, P < 0.001), with lower blood pressure (systolic 117.8 ± 15.8 vs. 126.3 ± 17.5 mmHg, P < 0.001; diastolic 75.3 ± 9.2 vs. 80.0 ± 10.0 mmHg, P = 0.001), lower triglyceride levels (1.17 mmol/L [0.06–6.88] vs. 1.61 mmol/L [0.15–14.99], P < 0.001), lower insulin secretion (FCP 0.32 ng/mL [0.01–1.57] vs. 0.51 [0.11–3.34], P < 0.001), and less MetS (39.5 vs. 70.1%, P < 0.001). However, when low GADA titer LADA were compared with type 2 diabetic patients (GADA-negative patients), with the exception of HDL cholesterol (1.26 ± 0.54 vs. 1.34 ± 0.70 mmol/L, P = 0.044), clinical features between them were not significantly different (Table 2).
(Enlarge Image)
Figure 3.
Bimodal GADA titer (log 10 transformed) in LADA patients. GADA positivity above or below 180 units/mL largely captured the two modes, with high GADA titer (≥180 units/mL) in 26.5% of patients (76 of 287) and a low GADA titer (<180 units/mL) in 73.5% (211 of 287).
HLA-DQ Genomic Background Differences
In these Chinese patients, as for Europeans, the frequency of total diabetes-susceptibility haplotypes (i.e., DQA1*03-DQB1*0302, DQA1*03-DQB1*0303, DQA1*03-DQB1*0401, and DQA1*05-DQB1*0201) was significantly higher in LADA (63.9% [115 of 180]) than in both type 2 diabetic (47.1% [82 of 174]) and control (43.2% [214 of 495]) subjects, while the frequency of diabetes-protective haplotypes (i.e., DQA1*0102-DQB1*0601, DQA1*0102-DQB1*0602, and DQA1*0601-DQB1*0301) in LADA (22.8% [41 of 180]) was significantly lower than in both type 2 diabetic (33.3% [58 of 174]) and control (32.7% [162 of 495]) subjects (Table 3). The frequency of HLA-DQ diabetes-susceptibility DQA1*05-DQB1*0201 was greater in high GADA titer than in low GADA titer patients (38.8% [19 of 49] vs. 13.7% [18 of 131], respectively, P < 0.001]) (Table 3). Comparing subjects from the south and north of China, LADA subjects had a similar frequency of HLA-DQ diabetes-susceptibility (69.3% [70 of 101] vs. 57.0% [45 of 79], respectively) and diabetes-protective (18.8% [19 of 101] vs. 27.8% [22 of 79], respectively) haplotypes (Table 4).